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Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

ABSTRACT: Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

SUBMITTER: Zanoni P

PROVIDER: S-EPMC4889017 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

Zanoni Paolo P Khetarpal Sumeet A SA Larach Daniel B DB Hancock-Cerutti William F WF Millar John S JS Cuchel Marina M DerOhannessian Stephanie S Kontush Anatol A Surendran Praveen P Saleheen Danish D Trompet Stella S Jukema J Wouter JW De Craen Anton A Deloukas Panos P Sattar Naveed N Ford Ian I Packard Chris C Majumder Abdullah al Shafi Aa Alam Dewan S DS Di Angelantonio Emanuele E Abecasis Goncalo G Chowdhury Rajiv R Erdmann Jeanette J Nordestgaard Børge G BG Nielsen Sune F SF Tybjærg-Hansen Anne A Schmidt Ruth Frikke RF Kuulasmaa Kari K Liu Dajiang J DJ Perola Markus M Blankenberg Stefan S Salomaa Veikko V Männistö Satu S Amouyel Philippe P Arveiler Dominique D Ferrieres Jean J Müller-Nurasyid Martina M Ferrario Marco M Kee Frank F Willer Cristen J CJ Samani Nilesh N Schunkert Heribert H Butterworth Adam S AS Howson Joanna M M JM Peloso Gina M GM Stitziel Nathan O NO Danesh John J Kathiresan Sekar S Rader Daniel J DJ

Science (New York, N.Y.) 20160301 6278

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying gene ...[more]

PMID: 26965621

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Project description:BackgroundAlthough HDL cholesterol concentrations are strongly and inversely associated with risk of coronary heart disease, interventions that raise HDL cholesterol do not reduce risk of coronary heart disease. HDL cholesterol efflux capacity-a prototypical measure of HDL function-has been associated with coronary heart disease after adjusting for HDL cholesterol, but its effect on incident coronary heart disease risk is uncertain.MethodsWe measured cholesterol efflux capacity and assessed its relation with vascular risk factors and incident coronary heart disease events in a nested case-control sample from the prospective EPIC-Norfolk study of 25 639 individuals aged 40-79 years, assessed in 1993-97 and followed up to 2009. We quantified cholesterol efflux capacity in 1745 patients with incident coronary heart disease and 1749 control participants free of any cardiovascular disorders by use of a validated ex-vivo radiotracer assay that involved incubation of cholesterol-labelled J774 macrophages with apoB-depleted serum from study participants.FindingsCholesterol efflux capacity was positively correlated with HDL cholesterol concentration (r=0·40; p<0·0001) and apoA-I concentration (r=0·22; p<0·0001). It was also inversely correlated with type 2 diabetes (r=-0·18; p<0·0001) and positively correlated with alcohol consumption (r=0·12; p<0·0001). In analyses comparing the top and bottom tertiles, cholesterol efflux capacity was significantly and inversely associated with incident coronary heart disease events, independent of age, sex, diabetes, hypertension, smoking and alcohol use, waist:hip ratio, BMI, LDL cholesterol concentration, log-triglycerides, and HDL cholesterol or apoA-I concentrations (odds ratio 0·64, 95% CI 0·51-0·80). After a similar multivariable adjustment the risk of incident coronary heart disease was 0·80 (95% CI 0·70-0·90) for a per-SD change in cholesterol efflux capacity.InterpretationHDL cholesterol efflux capacity might provide an alternative mechanism for therapeutic modulation of the HDL pathway beyond HDL cholesterol concentration to help reduce risk of coronary heart disease.FundingUS National Institutes of Health, UK Medical Research Council, Cancer Research UK.

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Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

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Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

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